The physiological role of metabotropic glutamate receptors is to control and regulate the presynaptic release and the postsynaptic effects of glutamate. Metabotropic glutamate 5 receptors (mGlu5 receptors) are primarily localized to the periphery of the post-synaptic densities of asymmetrical synapses (R. Lujan et al., Europ. J. Neurosci. (1996), 8, 1488-1500), where they function to enhance cellular excitability via interactions with ionotropic glutamate receptors and other postsynaptic processes. Because of their subcellular localization at the periphery of synapses, mGlu5 receptors further boost active synapses, whereas they remain mainly inactive during basal glutamatergic transmission. For this reason, mGlu5 receptor antagonists are hypothesized to be effective in states of glutamatergic hyperactivity whereas their effect on glutamatergic transmission under basal conditions is limited. On the other hand, mGlu5 agonists are effective in states of glutamatergic hypoactivity. mGlu5 receptor activation increases intracellular Ca2+ concentration by potentiation of NMDA currents and Ca2+ release from intracellular pools. Elevated intracellular Ca2+ levels determine the expression of NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) and hippocampal synaptic plasticity (Bikbaev et al., PlosOne (2008) 3, 2155). Expression of mGlu5 has been seen mainly in the cortex, hippocampus, subiculum, olfactory tubercle, striatum and nucleus accumbens (F. Ferraguti & R. Shigemoto, Cell Tisue Res (2006) 326, 483-504), which suggests an important contribution of mGlu5 receptors to cognitive and basal ganglia related functions. Based on the expression pattern of mGlu5 receptors and their biological function, mGlu5 antagonists have therapeutic potential for the treatment of diseases involving glutamatergic hyperactivity including anxiety, depression, pain addiction, gastro-esophagial reflux disease (GERD) Parkinson's disease, epilepsy, cancer, overactive bladder, aggression, fragile X or autism (Jaeschke et al., Expert Opin. Ther. Patents (2008) 18, 123-142). Several types of antagonists of the mGlu5 receptor have already been described in the literature.
WO2004/089471 discloses pyrazolopyrimidines which are claimed to act as antagonists of the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1).